Method for transforming pharmaceutical crystal forms

Abstract

The present invention provides gas-induced method for phase-transforming organic solids, such as pharmaceutical crystals. The inventive method subjects the polymorphs of pharmaceutical agents to various pressures of gases (such as CO2, N2O, and CH4) to induce phase transform with ease.

Description

[0001]This application claims the benefit of priority of U.S. Provisional Application No. 61 / 631,253, filed Dec. 30, 2011, the disclosure of which is hereby incorporated by reference as if written herein in its entirety.[0002]The present invention relates to method for transforming among different polymorphic forms of organic solids, more specifically, to a gas-induced transformation method of pharmaceutical crystals.[0003]The phenomenon of polymorphism, the ability of a compound to crystallize into more than one distinct crystal species, is a major factor in the pharmaceutical industry, as different polymorphs can display markedly disparate stabilities, solubility, and / or bioavailability. Different physical forms can be classified as polymorphs or pseudopolymorphs (solvates and hydrates). Polymorphs have the same chemical composition but different crystal structures. Pseudopolymorphs are crystalline adducts that contain solvent molecules (water in the case of hydrates) within the c...

AI Technical Summary

Benefits of technology

[0014]The invention provides a new and improved method for controlling phase transitions among the polymorphic forms of an organic solid. The inventive method employs simple pressurization of gas (such as CO2) to induce transformations among different polymorphic forms of an organic solid with ease. More specifically, the method of transforming an organic solid from a first polymorphic form to a second polymorphic form comprises the step of subjecting said organic solid to a pressurized gas under low to moderate pressure at room temperature to a mildly elevated temperature for a period of time. According to one embodiment of the invention, the pressurized gas may be CO2, N2O, or CH4, and the pressure may be 1 atm and up, whereas when the pressure is elevated, the temperature may be lowered with shortened durations.

Problems solved by technology

Further, some materials can only be desolvated through techniques that are difficult to apply on an industrial scale.

From a thermodynamic point of view, the amorphous forms have a higher energy content than the crystalline state, leading to lower stability and higher reactivity.

For example, in the case of novobiocin, the crystalline form is poorly absorbed and does not provide therapeutically adequate plasma levels upon oral administration.

Pharmaceutical companies quite often must face unexpected and undesired productive and / or clinical problems due to the appearance of crystal forms different from that used for drug product development.

There are countless examples of biologically active compounds that have proven to be difficult to control in the solid state, wherein the polymorph formed during the industrial process may be not be the polymorph desired for the dosage form.

The stable solvent-free marketing agent is currently isolated by stirring the 1:1 ethanol hydrate of 2 (that is prone to decomposition) in water, followed by filtration and intensive drying to remove surface water, which is difficult for industry scale process.

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